Abstract 2248: Activity of targeted agents in PIK3R1 mutated patient-derived xenografts
Authors: Abde M. Abukhdeir, Melody Cobleigh
Journal: Cancer Research (2023)

Abstract Background: The PIK3R1 gene is genetically altered in up to ~5% of triple negative breast cancers (TNBCs). We previously reported that breast cancer cells lacking protein expression of PIK3R1 had elevated levels of activated MEK, sensitizing them to the MEK inhibitor trametinib. To better understand whether MEK inhibition is a therapeutic option for breast cancer patients with mutated PIK3R1, we conducted a pilot study using the newer generation MEK inhibitor, binimetinib, in a PDX mouse model and found that mutations in PIK3R1 sensitized these PDXs to binimetinib. Alpelisib is FDA-approved for use in breast cancers harboring certain mutations in PIK3CA. Since PIK3R1 and PIK3CA form the PI3K complex, we reasoned that alpelisib may also have activity in mutant-PIK3R1 breast cancers. In this study, we aimed to test binimetinib, alpelisib and the combination in PDX models harboring PIK3R1 mutations. Methods: Three PDX models derived from TNBCs were tested in athymic nude-foxn1nu (Immune-compromised) mice. All PDX models had wild-type PIK3CA and PTEN. Model 1 was wild type for PIK3R1, while Models 2 and 3 harbored PIK3R1mutations c.1357_1389del and c.1705_1740del, respectively. PDX models were treated with vehicle control, binimetinib alone (10 mg/kg BID), alpelisib alone (35 mg/kg QD), or binimetinib and alpelisib in combination. Animals were treated orally daily for at least 28 days. Tumor volumes and animal weights were measured twice weekly until study endpoint. Results: At the time of this publication, Models 1 and 2 had not reached the study endpoint. Final results will be presented at the meeting. Interim ANOVA endpoint analysis revealed no significant differences across treatment arms in Model 1 (wild type PIK3R1). However, a significant effect of treatment was observed in Models 2 and 3 (mutant PIK3R1; p=0.040 and p=0.00001, respectively). Tukey’s test revealed that the treatment effect in Model 2 resulted from the vehicle control compared to the combination arm [(binimetinib + alpelisib), p=0.016], while in Model 3, a highly significant effect of treatment was observed between vehicle control and each treatment arm (p&amp;lt;0.000001). Finally, in Model 3, the drug combination significantly decreased tumor growth compared to each agent alone (p=0.033 and p=0.027 for binimetinib and alpelisib, respectively). Conclusions: Mutations in PIK3R1 sensitize TNBCs to MEK inhibitors like binimetinib. In the absence of functional PIK3R1, aberrant PI3K signaling occurs, which explains the sensitivity of breast cancers that are PIK3CA wild-type and PIK3R1 mutant to alpelisib. The combination of both MEK and PIK3CA inhibition appears to be an effective combination therapy in TNBCs harboring mutations in PIK3R1. AMA is employed by the U.S. FDA, but contributed to this publication in his own capacity. The views expressed are his own and do not necessarily represent the views of the Food and Drug Administration or the United States Government. Citation Format: Abde M. Abukhdeir, Melody Cobleigh. Activity of targeted agents in PIK3R1 mutated patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2248.